discription on basic neurobiology of axons and neurons and further their growth and death in human body

1. THE GROWTH AND GUIDANCE OF AXONS
Nitish kumar
M.Sc
Neurotechnology
JIPMER

2. CONTENTS
Differences Between Axons and Dendrites Emerge Early in
Development
Patterning of the dendrites by extrinsic and intrinsic factors
The Growth Cone
Molecular Cues Guiding Axons to Their Targets
Axons From Some Spinal Neurons And Guided Across the Midline
1. Netrins Direct Developing Commissural Axons Across the Midline
2. Chemoattractant and Chemorepellent Factors Pattern the Midline

3. INTRODUCTION
In last class we saw how neurons are generated in appropriate
numbers, at correct times, and in the right places.
These early developmental steps set the stage for later events that
direct neurons to form functional connections with target cells.
To form connections, neurons have to extend long processes—axons
and dendrites—which permit connectivity with postsynaptic cells and
synaptic input from other neurons

4. DIFFERENCES BETWEEN AXONS AND
DENDRITES EMERGE EARLY IN
DEVELOPMENT
•The processes of neurons vary enormously in their length, thickness,
branching pattern, and molecular architecture.
•Most neuronal processes fit into one of two functional categories:
axons and dendrites
•More than a century ago, Santiago Ramón y Cajal hypothesized that
this distinction underlies the ability of neurons to transmit
information in a particular direction.
• He wrote that “the transmission of the nerve impulse is always from
the dendritic branches and the cell body to the axon.” formalized as
the law of dynamic polarization.

5. CONTD.
•Cytoskeletal proteins that maintain elongated processes and drive
growth are central to the process of differentiation.
• If the actin filaments in an early neurite are destabilized, the
cytoskeleton becomes reconfigured in a way that commits the neurite
to becoming the axon; secondarily, the remaining neurites react by
becoming dendrites.
•Axonal specification is a key event in neuronal polarization and
signals from newly formed axons both suppress the generation of
additional axons and promote dendrite formation.

6. CONTD.
In the developing brain, the local release of semaphorins and other
axonal guidance factors, may help to orient dendrites.
The job of the Par protein complex is to link these extracellular
signals to the cellular machinery that rearranges the cytoskeleton, a
process achieved in part through the regulation of proteins that
modify actin or tubulin functions.
Both the Tau protein in axons and the MAP2 protein in dendrites
associate with and affect microtubules.

8. PATTERNING OF THE DENDRITES BY
EXTRINSIC AND INTRINSIC FACTORS
Once polarization occurs, dendrites grow and mature, acquiring the
structural features that distinguish them from
Nascent dendrites form branched arbors, with their branches
generally being more numerous and closer to the cell body than
those of axons
 small protrusions called spines extend from the distal branches of
many dendrites.
Finally, some dendritic branches are retracted or “pruned” to give the
arbor its final and definitive shape

10. CONTD.
In both invertebrates and vertebrates, some transcription factors are
selectively expressed by specific neuronal types and appear to be
devoted to controlling the size, shape, and complexity of their
dendritic arbors.
A second mechanism for establishing the pattern of dendritic arbors
is the recognition of one dendrite by others of the same cell. In some
neurons, dendrites are spaced evenly with respect to each other, an
arrangement that allows them to sample inputs efficiently without
major gaps or clumps.
In many cases, this process, called self-avoidance, occurs through a
mechanism in which branches belonging to the same neuron repel
each other.

11. CONTD.
The dendrites of neighboring neurons also provide cues. In many
cases, the dendrites of a particular neuron type cover a surface with
minimal overlap, a spacing pattern called tiling. The tiling of
dendrites is conceptually related to self-avoidance.
Tiling allows each class of neuron to receive information from the
entire surface or area it innervates. Tiling of a region by the dendrites
of one class of neuron also avoids the confusion that could arise if
the dendrites of many different neurons occupied the same area

12. THE GROWTH CONE
Once an axon forms, it begins to grow toward its synaptic target.
The key neuronal element responsible for axonal growth is a
specialized structure at the tip of the axon called the growth cone.
Both axons and dendrites uses the growth cone extensively for
elongation but those linked with axons have been studied more
intensively.
It is now known as that the growth cone is both a sensory structure
that receives directional cues from the environment and a motor
structure whose activity drives axon elongation.

13. CONTD.
Growth cones have three main compartments.
1. Their central core is rich in microtubules, mitochondria, and other
organelles.
2. Long slender extensions called filopodia project from the body of
the growth cone.
3. Between the filopodia lie lamellipodia, which are also motile and
give the growth cone its characteristic ruffled appearance.
- Growth cones sense environmental signals through their
filopodia: rod-like, actin-rich, membrane-limited structures that are
highly motile. Their surface membranes bear receptors for the
molecules that serve as directional cues for the axon.

14. CONTD.
Their length—tens of micrometers in some cases—permits the
filopodia to sample environments far in advance of the central core of
the growth core.
Their rapid movements permit them to compile a detailed inventory
of the environment, and their flexibility permits them to navigate
around cells and other obstacles.
When filopodia encounter signals in the environment, the growth
cone is stimulated to advance, retract, or turn. Several motors power
these orienting behaviors. One source of power is the movement of
actin along myosin.

16. CONTD.
Integrin receptors couple to actin in growth cones when they bind
molecules associated with the surface of adjoining cells or the
extracellular matrix, thereby influencing motility.
Other important step in the process is the ability of ligand binding to
stimulate the formation, accumulation, and even breakdown of
soluble intracellular molecules that function as second messenger(eg:
calcium).

17. MOLECULAR CUES GUIDING AXONS
TO THEIR TARGETS
Today, few scientists believe that stereotaxis or resonance is a
crucial force in initial patterning of neuronal circuits.
Guidance cues can be presented on cell surfaces, in the extracellular
matrix, or in soluble form. They interact with receptors embedded in
the growth cone membrane to promote or inhibit outgrowth of the
axon.
The ligands can speed or slow growth. Ligands presented to one
side of the growth cone can result in local activation or inhibition,
leading to turning

20. CONTD.

23. AXONS FROM SOME SPINAL NEURONS
AND GUIDED ACROSS THE MIDLINE
•One of the fundamental features of the central nervous system is the
need to coordinate activity on both sides of the body. To accomplish
this task, certain axons need to project to the opposite side.
•This crossing can be seen in case of commissural neurons and optic
chaisma.

24. NETRINS DIRECT DEVELOPING
COMMISSURAL AXONS ACROSS
THE MIDLINE
Many of the neurons that send axons across the ventral midline are
generated in the dorsal half of the spinal cord.
One of the chemotactic factors termed as protein neutrin-1 is
expressed by cells of the floor plate as well as by progenitors along
the ventral midline.
The neutrin functions to attracts commissural axons. Vertebrate
netrin receptors are related to the unc-5 and unc-40 receptors.
It may act as both a secreted factor (chemotaxis) and a membrane
guidance molecule (haptotaxis) to guide the axons of commissural
neurons to the floor plate.

25. CHEMOATTRACTANT AND
CHEMOREPELLENT FACTORS
PATTERN THE MIDLINE
One group consists of bone morphogenetic proteins(BMP), which are
secreted by the roof plate. They act as repellents, directing
commissural axons ventrally as they begin their journey.
Additional factors from the floor plate, such as the hedgehog
proteins initially involved in patterning the spinal cord may
collaborate with netrins at a later stage, serving as axonal attractants.

27. CONTD.
Once commissural axons reach the midline, they find themselves
exposed to the highest available levels of netrin-1 and sonic
hedgehog.
Yet this netrin-rich environment does not keep the axons at the
midline indefinitely.
 Instead they cross to the other side of the spinal cord, even while
their contralateral counterparts are navigating up the netrin
chemoattractant gradient

28. CONTD.
This puzzling behavior is explained by the fact that growth cones
change their responsiveness to attractive and repellent signals as a
consequence of exposure to floor plate signals.
Once axons arrive at the floor plate, they become sensitive to Slit, a
chemorepellent signal secreted by floor plate cells.
Before commissural axons reach the floor plate, the Robo proteins
that serve as Slit receptors are kept inactive by expression of a
related protein, Rig-1.
. As axons reach the floor plate, levels of Rig-1 on their surface
decline, unleashing Robo activity and causing axons to respond to the
repellant actions of Slit.
 This repellent action propels growth cones down the Slit gradient
into the contralateral side of the spinal cord.

30. CONTD.
Finally, once axons have left the floor plate, they turn rostrally toward
their eventual synaptic targets in the brain.
A rostrocaudal gradient of Wnt proteins expressed by floor plate cells
appears to direct axon growth rostrally at the ventral midline
Thus, different cues guide axons during distinct phases of their
overall trajectory. This same process is presumably played out for
hundreds and even thousands of classes of neurons to establish the
mature pattern of brain wiring.

31. SUMMARY
1. As neurons extend processes, one generally becomes an axon and the
others become dendrites. This process is called polarization. The two
types of processes differ in structure and molecular architecture as well
as function.
2. Cell types differ markedly in the shape, size, and branching patterns of
their dendrites. Type-specific dendritic features arise both from intrinsic
differences in transcriptional programs among types and from extrinsic
influences on the developing dendrites.
3. Growth cones at the tips of axons serve as both sensory and motor
elements to guide axons to their destinations. Cytoskeletal elements of
the growth cone, including actin and myosin, propel the growth.
4. Receptors on the growth cone recognize and bind ligands in the
environment through which the axon is extending, guiding the growth.
These interactions lead to generation of their second messengers that
mediate growth, turning and stopping of the growth cone, and branching
of the axon

32. CONTD.
5. Some growth cones contain protein synthetic machinery including
messenger RNAs. In these cases, receptors can promote local synthesis of
specific proteins that mediate growth or turning.
6. Ligand–receptor pairs include several key families of molecules including
cadherins, Slits and their Robo receptors, semaphorins and their plexin
receptors, and ephrins and their Eph kinase receptors.
7. The growth of an axon to a distant target is broken into discrete shorter
steps. At each step, molecules on the surface of or secreted by
neighboring structures guide the axon. They can also lead to alterations
in the growth cone’s complement of receptors, allowing it to respond to
different sets of cues at the subsequent stage.
8. Both attractive and repellent molecules guide axons across midline
structures, a process called decussation. Evolutionarily conserved signals
include Slits, netrins, and Wnts. Mutations in genes that encode these
ligands and receptors can result in developmental neurological disorders.

33. REFERENCES
PRINCIPLES OF NEURAL SCIENCE sixth edition edited by ERIC R. Kandel
john d. Koester sarah h. Mack steven a. Siegelbau.